Treatment of rodents with the immunosuppressive agent cyclosporine A (CsA) following syngeneic bone marrow transplantation results in the development of a graft-versus-host (GVHD)-Iike syndrome, termed syngeneic GVHD (SGVHD). This inducible disease is currently being explored clinically and experimentally for anti-tumor potential. We have recently demonstrated the development of a TH1-like (IL-12, IFN-gamma) cytokine response during the course of murine SGVHD with macrophage activation being central to the development of SGVHD. Since CsA therapy induces oxidative stress and oxidative stress has been shown to activate the production of proinflammatory cytokines by macrophages and other cell types, studies will test the hypothesis that CsA-induced oxidative stress directly participates in the SGVHD induction process. Furthermore, recent findings have shown that distinct T cell changes occur in the periphery and colon of diseased animals. In vivo depletion and adoptive transfer studies will address the role of T cells in the activation of macrophages and the development of SGVHD. We have demonstrated that animals with SGVHD reject a primary but not a secondary challenge with a class II- B cell lymphoma, suggesting the involvement of non-specific effector mechanisms. The nature and specificity of the anti-tumor effector mechanism(s) (cytokine and lymphoid) present in tumor-bearing SGVHD animals will be analyzed. Furthermore, for SGVHD-mediated graft-versus-tumor (GVT) to be optimally effective, the development of memory anti-tumor immunity will be required. We hypothesize that reduced numbers of T cells at the time of tumor challenge, low amount of tumor antigen being introduced into the SGVHD/GVL system, the lack of tumor class II molecules, or the development of regulatory mechanisms may contribute in part to the inability to develop memory anti-immunity in this model. Experiments will be designed to address each of these hypotheses. The analysis of murine SGVHD should present a unique opportunity to study the immune responses that participate in the development.